The protective value of a hypothetical HIV vaccine, capable of functioning prior to virus induced injury to the immune system, was modeled by administering the reverse transcriptase inhibitor, tenofovir, 48h post SIV inoculation of six rhesus macaques. Although virus replication (monitored by RT-PCR and cell associated DNA PCR) were effectively suppressed, memory CD4+ T cells in the blood and at an effector site (lung) were preserved, and evidence of SIV-specific T cells responses was observed during the period of tenofovir administration, plasma viremia became detectable in all six of the treated animals immediately following cessation of anti-retroviral therapy. Unexpectedly, the viral set points in the tenofovir treated monkeys were established at two distinct levels. Three animals (non-controllers) had plasma viral RNA loads in the 105 to 106 RNA copies/ml range (similar to untreated SIV inoculated macaques) and three monkeys (controllers) had viral loads in 103 RNA copies/ml range. Analyses of the MHC class I alleles in the tenofovir treated cohort revealed that two of the three controllers carried genes (Mamu-B*08, Mamu-B*29, and Mamu-A*02) previously associated with suppression of virus replication in SIV inoculated rhesus macaques (Ref 8). Nevertheless, two of the controller macaques began to experience loss of memory CD4+ T cells at months 9 and 11 post-challenge, respectively, that was accompanied by marked increases in the levels of their set-point viremia to the 105 to 106 range. At week 80 PI, only two tenofovir treated animals, both bearing protective MHC alleles, remain alive.